Research in the major genetic model systems has revealed a strong and consistent association between dietary restriction, mutations that extend life span, and resistance to multiple stresses. Here we propose to investigate the mechanisms of aging with focus on starvation-dependent protection against oxidative damage and life span. We propose to continue our work to establish which combination of treatments and genetic manipulations causes the maximum resistance to toxins and identify the underiying mechanisms with focus on ER stress. We will continue and expand our mammalian cell and mouse studies to determine the role of short-term starvation on cellular senescence and aging in murine models and identify the mechanisms of starvation-dependent protection. We will also test the hypothesis that pathways analogous to those identified in yeast can protect normal but not cells with constitutively active pro-aging pathways (cancer cells) against oxidative damage and chemotherapy (Differential Stress Resistance, DSR) and study the mechanisms involved. Because older subjects are particularly sensitive to toxins, we will study DSR in young and old mice to identify interventions that can protect old organisms against cytotoxicity. The collaborations with Cohen and Lee will continue to introduce novel ideas, approaches, and research tools to our laboratory and provide the synergism necessary to accelerate our research. This collaborative biogerontology-based approach has the potential to identify new genetic pathways and mechanisms relevant to the basic biology of aging but also interventions that can be applied to the development of improved treatments and prevention of age-related diseases. RELEVANCE (See instructions): Research on age-related diseases focuses primarily on the damaged cells or tissues affected by the disease. Here we propose to take a biogerontology-based approach to instead focus on the mechanisms of protection of all the healthy cells ofthe organism. These studies will help identify strategies, genetic pathways and drug targets to protect the organism against the age-dependent damage and diseases caused by endogenous as well as exogenous toxins.